Pharmaceutical composition

ABSTRACT

A pharmaceutical composition comprising: (A) an androgen; (B) a cyclic enhancer of the type used in the compositions and methods claimed by U.S. Pat. No. 5,023,252 to Hsieh; and (C) a thickening agent; including, for example, a composition in which the cyclic enhancer is a macrocyclic ester or a macrocyclic ketone; the use of the composition to treat a condition, for example, male hypogonadism, in a patient by applying the composition to the membrane of the patient; and a method for making the composition.

FIELD OF THE INVENTION

The present invention relates to a composition useful for the deliveryof an androgen. More particularly, the present invention relates to apharmaceutical composition comprising an androgen and an enhancer, thatis, a material which is capable of increasing the rate of passage of anandrogen through a body membrane.

Androgens include, for example, 17β-hydroxyandrost-4-en-3-one, commonlyknown as testosterone, and dihydrotestosterone (DHT), a metabolite oftestosterone. Testosterone is a naturally-occurring androgen which issecreted in males and, to a much lesser extent, in females. In males,testosterone and DHT are responsible for normal growth and developmentof the male sex organs and for maintenance of secondary sexcharacteristics. In females, testosterone and DHT are believed to beimportant for normal growth, sexual desire, and sexual function. Inaddition, androgens promote retention of nitrogen, sodium, potassium,and phosphorus, and decrease the urinary excretion of calcium. Androgenshave been reported to also increase protein anabolism, decrease proteincatabolism, and stimulate the production of red blood cells.

In the blood serum, testosterone exists primarily bound to a protein,typically albumin or sex hormone binding protein. Unbound testosteroneis referred to as “free testosterone” (FT). The term “totaltestosterone” (T) refers to the total amount of testosterone in theblood serum, that is, the combined amount of protein-bound testosteroneand free testosterone. The typical half-life of testosterone in theblood serum ranges from 10 to 100 minutes.

Androgens such as testosterone and DHT bind to androgen receptors oncells. The resulting androgen-receptor complex regulates gonadotropinsecretion and spermatogenesis. The androgen-receptor complex isresponsible also for external virilization and for most androgen actionsduring sexual maturation and adult life. DHT is an especially potentandrogen because it binds with greater affinity to androgen receptorsthan testosterone does.

Testosterone production is stimulated by luteinizing hormone (LH). It isbelieved that follicle stimulating hormone (FSH) stimulates testosteroneproduction also. Testosterone concentrations in the blood serum areregulated in part by a negative-feedback pathway in which testosteroneinhibits the formation and/or secretion of luteinizing hormone-releasinghormone (LHRH). LHRH stimulates the secretion of LH by the pituitarygland. Testosterone acts also by regulating the sensitivity of thepituitary gland to LHRH.

Male hypogonadism is a disorder in males resulting from or characterizedby abnormally-decreased functional activity of the gonads. Malehypogonadism is manifested in the form of below-normal concentration oftestosterone in the blood serum. The U.S. Federal Food and DrugAdministration estimates that about 4 to 5 million Americans suffer frommale hypogonadism and that male hypogonadism affects about 5 in every1,000 men. It is believed that male hypogonadism affects 1 out of every5 men aged over 50. Primary male hypogonadism is caused by testicularfailure. Secondary male hypogonadism is caused by idiopathicgonadotropin, LHRH deficiency, or pituitary-hypothalamic injury. Variousother causes of male hypogonadism include, for example, decline in thenumber of Leydig cells in the testes due to old age, and primary organiccauses. Symptoms associated with male hypogonadism include decreasedsexual desire with or without impotence, depression, decreased libido,fatigue and loss of energy, erectile dysfunction, mood depression,osteoporosis, reduced lean body mass, decreased muscle mass, decreasedbone density, and regression of secondary sex characteristics.

Females with below-average androgen concentration in the blood serumsuffer also from disorders related to androgen deficiency. Causes ofandrogen deficiency in females include aging, oophorectomy, and ovaryfailure. Symptoms associated with female androgen deficiency includefemale sexual dysfunction, lack of desire, and muscle wasting.

Normal concentration of androgen in the blood serum may be achieved inpatients with the administration of exogenous androgen. It has been welldocumented that administration of exogenous androgen results in themaintenance or restoration of male secondary sexual characteristics,sexual behavior, energy, mood, and muscle development as well as adecrease in the percentage of fat in body composition and an improvementin bone density.

Various methods for administering exogenous androgen have beendeveloped. Optimally, such methods should not only raise theconcentration of androgen in the blood serum but also, because of theshort half-life of androgen, allow for normalization of androgendelivery into the blood serum over an extended period of time, thusmaintaining an effective concentration of androgen in the blood serumover an appropriate period of time and avoiding undesirable effectswhich may result from sudden increases and declines in androgenconcentration in the blood serum. In addition, such methods preferablyresult in minimal or no adverse effects, such as irritation, damage tothe body, and pain.

The oral delivery of exogenous androgen has been used to treathypogonadism. Androgen delivered orally, however, is first absorbed fromthe gastrointestinal tract. Such absorption is irregular and thus oftenresults in sudden increases and declines in androgen concentration inthe blood serum. Furthermore, androgen which is absorbed through thegastrointestinal tract passes into the portal circulation and isdegraded rapidly by the liver. Only a relatively small amount ofandrogen enters the systemic circulation. The passage of androgenthrough the portal circulation system and the liver may also result inadverse effects.

Exogenous androgen may alternatively be delivered parenterally directlyinto the systemic circulation. Such delivery allows for androgen toenter the systemic circulation directly, avoiding the gastrointestinaltract and the liver. Androgen delivered parenterally, however, isabsorbed rapidly from the injection vehicle into the blood serum thusmaking a sustained delivery of androgen difficult to achieve andresulting in a sudden increase in androgen concentrations in the bloodserum followed by a gradual decline. The rate of androgen absorption canbe retarded with the use of esterified forms of androgen. Esterifiedforms of androgen are more soluble than non-esterified forms of androgenin the lipidic vehicles typically used for parenteral delivery. Suchesterified forms of androgen, however, are rapidly de-esterified in theblood serum and thus sustained delivery of androgen remains difficult tomaintain. In addition, the absorption of androgen from the injectionvehicle is irregular, thus leading to sudden fluctuations in androgenconcentration in the blood serum. Furthermore, parenteral delivery isuncomfortable and leads to problems of patient compliance.

The transdermal delivery of androgen avoids many of the disadvantages oforal and parenteral delivery. Such delivery is relatively painless andallows androgen to enter systemic circulation without having to firstpass through the gastrointestinal tract or the liver.

One method for transdermal delivery of androgen involves the use of atransdermal patch which is adhered to the surface of the skin of thepatient and which contains a reservoir of androgen that is absorbed bythe skin. Such patches, however, cause irritation of the skin, are oftenpainful to remove, and are dislodged easily. Moreover, such patches areindiscrete in that they are noticeable when not covered, are large andbulky, and may leave a discolored area of skin after removal. Inaddition, the compositions contained in such patches are also oftenirritating to the skin.

Another method for transdermal delivery of androgen involves theapplication directly to the skin of an androgen-containing compositionin the form of a gel. Such a gel is referred to herein as a “topicalgel” to distinguish it from other compositions which are in a gel formand which are contained within an article that is applied to the skin,for example, a transdermal patch.

The present invention relates to the provision of an improvedandrogen-containing composition which can be applied directly to theskin for sustained delivery of androgen to an individual in needthereof.

Reported Developments

There have been developed androgen-containing compositions in the formof a topical gel applied directly to the skin, for example, to the back,shoulders, upper arms, abdomen, or thighs. The use of such topical gelsovercomes the previously-mentioned negative effects of a patch as wellas the previously-mentioned negative pharmacokinetic effects of oral andparenteral androgen administration. In addition, since such a topicalgel is typically in contact with a larger area of the skin relative tothat contacted by a patch and, since the skin serves as an appropriatereservoir for the androgen delivered, a consistent normalization ofandrogen delivery into the blood serum over an extended period of timeis able to be achieved.

The ability of an androgen gel to deliver androgen effectively is oftendependent on whether an enhancer, that is, a material which is capableof increasing the rate of passage of androgen through the skin or otherbody membrane, is used and the type of enhancer used. Examples oftopical androgen gels include those described in U.S. Pat. No. 5,968,919to Samour et al. and U.S. Pat. No. 6,503,894 to Dudley et al. The '919patent describes a topical testosterone gel comprising also a dioxolaneor a dioxane compound which functions as an enhancer. The topicaltestosterone gel described in the '894 patent (sold as AndroGel® bySolvay Pharmaceuticals, Inc., Marietta, Ga., U.S.A.) also contains anenhancer, namely, isopropyl myristate.

Disadvantages associated with the aforementioned topical androgen gelsinclude, for example, the inconsistency of the gels and the lack ofemollient properties; their use leads to drying of the skin and skinirritation. In addition, the gel of the '894 patent is capable ofdelivering a relatively low amount of testosterone through the skin andthe gel of the '919 patent contains an enhancer which tends to irritatethe skin.

SUMMARY OF THE INVENTION

In accordance with this invention, there is provided a pharmaceuticalcomposition comprising: (A) an androgen; (B) a cyclic enhancer of thetype described in U.S. Pat. No. 5,023,252 to Hsieh (assigned to the sameassignee as that of the present invention); and (C) a thickening agent.In preferred form, such a composition exists in the form of a gel andcomprises an enhancer which is a cyclic ester or a cyclic ketone.

Another aspect of the present invention is a unit dose formulation whichis effective in supplying testosterone transdermally to the blood of amale patient such that, following a single application of the unit doseto the patient, the amount of circulating testosterone (AUC₀₋₂₄) in theblood serum of the patient achieved in the 24-hour period following theapplication is about 100 to about 35,000 ng·h/dL greater than the amountof circulating testosterone (AUC₀₋₂₄) in the blood serum of the patientthat would have been achieved in the same 24-hour period had the dosenot been administered, said unit dose comprising up to about 1% byweight testosterone, about 0.01 to about 25% by weight of a cyclicenhancer of the type described in U.S. Pat. No. 5,023,252 to Hsieh, andabout 0.1 to about 10% by weight of thickening agent, said testosteronebeing present in said unit dose in an amount of about 1 to about 300 mg.

Another aspect of the present invention is a unit dose formulation whichis effective in supplying testosterone transdermally to the blood of afemale patient such that, following a single application of the unitdose to the patient, the amount of circulating testosterone (AUC₀₋₂₄) inthe blood serum of the patient achieved in the 24-hour period followingthe application is about 0.10 to about 11,700 ng·h/dL greater than theamount of circulating testosterone (AUC₀₋₂₄) in the blood serum of thepatient that would have been achieved in the same 24-hour period had thedose not been administered, said unit dose comprising up to about 1% byweight testosterone, about 0.01 to about 25% by weight of a cyclicenhancer of the type described in U.S. Pat. No. 5,023,252 to Hsieh, andabout 0.1 to about 10% by weight of thickening agent, said testosteronebeing present in said unit dose in an amount of about 0.01 to about 100mg.

Another aspect of the present invention is a unit dose formulation whichis effective in supplying dihydrotestosterone transdermally to the bloodof a male patient such that, following a single application of the unitdose to the patient, the amount of circulating dihydrotestosterone(AUC₀₋₂₄) in the blood serum of the patient achieved in the 24-hourperiod following the application is about 11,625 to about 465,000pg·h/mL greater than the amount of circulating dihydrotestosterone(AUC₀₋₂₄) in the blood serum of the patient that would have beenachieved in the same 24-hour period had the dose not been administered,said unit dose comprising up to about 1% by weight dihydrotestosterone,about 0.01 to about 25% by weight of a cyclic enhancer of the typedescribed in U.S. Pat. No. 5,023,252 to Hsieh, and about 0.1 to about10% by weight of thickening agent, said dihydrotestosterone beingpresent in said unit dose in an amount of about 5 to about 200 mg.

Another aspect of the present invention is a unit dose formulation whichis effective in supplying dihydrotestosterone transdermally to the bloodof a female patient such that, following a single application of theunit dose to the patient, the average dihydrotestosterone concentration(AUC₀₋₂₄) in the blood serum of the patient achieved in the 24-hourperiod following the application is about 11.6 about 232,500 pg·h/mLgreater than the average dihydrotestosterone concentration (AUC₀₋₂₄) inthe blood serum of the patient that would have been achieved in the same24-hour period had the dose not been administered, said unit dosecomprising up to about 1% by weight dihydrotestosterone, about 0.01 toabout 25% by weight of a cyclic enhancer of the type described in U.S.Pat. No. 5,023,252 to Hsieh, and about 0.1 to about 10% by weight ofthickening agent, said dihydrotestosterone being present in said unitdose in an amount of about 0.005 to about 100 mg.

Yet another aspect of the present invention is the provision of a methodfor treating a condition in a patient comprising the step of deliveringto said patient a composition comprising an androgen, a cyclic enhancerof the type described in U.S. Pat. No. 5,023,252 to Hsieh, and athickening agent.

Yet another aspect of the present invention is the provision of a methodfor treating a condition in a patient comprising the step of applying,once daily, to the shoulder or upper arm of a patient, a unit doseformulation which is effective in supplying testosterone transdermallyto the blood of a patient such that, following a single application ofthe unit dose to the patient, the amount of circulating testosterone(AUC₀₋₂₄) in the blood serum of the patient achieved in the 24-hourperiod following the application is about 100 to about 35,000 ng·h/dLgreater than the amount of circulating testosterone (AUC₀₋₂₄) in theblood serum of the patient that would have been achieved in the same24-hour period had the dose not been administered, said unit dosecomprising up to about 1% by weight testosterone, about 0.01 to about25% by weight of a cyclic enhancer of the type described in U.S. Pat.No. 5,023,252, and about 0.1 to about 10% by weight of thickening agent,said testosterone being present in said unit dose in an amount of about1 to about 300 mg.

Yet another aspect of the present invention is a method for making acomposition useful for treating a condition in a patient comprising thestep of mixing an androgen, a cyclic enhancer of the type described inU.S. Pat. No. 5,023,252 to Hsieh, and a thickening agent.

DETAILED DESCRIPTION OF DRAWINGS

FIG. 1 is a graph comparing the 48-hour total testosteronepharmacokinetic profile for a first group of hypogonadal men followingtreatment with a single 5.0 g dose of a composition of the presentinvention with the 48-hour total testosterone pharmacokinetic profilefor a second group of hypogonadal men following treatment with a single5.0 g dose of the composition described in Comparative Example C-1below.

FIG. 2 is a graph comparing the mean change in body composition frombaseline to Day 90 for patients treated daily using 5 g/day of acomposition of the present invention, patients treated using 10 g/day ofthis composition, patients treated using 2 patches/day containing thecomposition described in Comparative Example C-2 below, and patients whoapplied 10 g/day of a placebo composition.

FIG. 3 is a graph comparing skin irritation scores at Days 30, 60, and90 for patients treated daily using 5 g/day of a composition of thepresent invention, patients treated using 10 g/day of this composition,patients treated using 2 patches/day containing the compositiondescribed in Comparative Example C-2 below, and patients who applied 10g/day of a placebo composition.

DETAILED DESCRIPTION OF THE INVENTION

The composition of the present invention comprises an androgen. As usedherein, the term “androgen” refers to: testosterone; dihydrotestosterone(DHT); and precursors, congeners, salts, complexes, and analogs oftestosterone and DHT. Examples of precursors of testosterone and DHTinclude, for example, DHEA, pregnenolone, progesterone,17-OH-progesterone, and androsterone. Examples of analogs oftestosterone and DHT include: testosterone esters, including straightand branched C₁₋₁₈ alkyl esters (herein referred to as “simple alkylesters”), for example, testosterone enanthate, testosterone propionate,testosterone undecanoate, and testosterone heptylate, and cycloaliphaticesters, for example, testosterone cypionate, testosterone cyclopentylalkyl ester, and testosterone cyclohexyl alkyl ester; and the analogousesters of DHT.

Androgen is present in the composition in a pharmaceutically-effectiveconcentration. For guideline purposes, it is believed most applicationswill involve the use of the androgen in an amount of about 0.01 to about15 wt. % of the composition, more likely an amount of about 0.01 toabout 10 wt. % of the composition, and most likely in an amount of about0.1 to about 5 wt. % of the composition.

The composition of the present invention comprises also an enhancer,that is a compound capable of increasing the rate of passage of anandrogen through a body membrane, for example, skin and mucousmembranes. The enhancer of the present invention is a compound of thestructural formula:

wherein X and Y are oxygen, sulfur or an imino group of the structure

or ═N—R; with the proviso that when Y is an imino group, X is an iminogroup, and when Y is sulfur, X is sulfur or an imino group; A is a grouphaving the structure

wherein X and Y are as defined above; m and n are integers having avalue from 1 to 20 and the sum of m+n is not greater than 25; p is aninteger having a value of 0 or 1; q is an integer having a value of 0 or1; r is an integer having a value of 0 or 1; and each of R, R₁, R₂, R₃,R₄, R₅, and R₆ is independently hydrogen or an alkyl group having from 1to 6 carbon atoms which may be straight chained or branched, providedthat only one of R₁ to R₆ can be alkyl group; with the proviso that whenp, q and r are 0 and Y is oxygen, then m+n is at least 11; and with thefurther proviso that when X is an imino group, q is equal to 1, Y isoxygen, and p and r are 0, then m+n is at least 11.

Enhancers of the above structural formula are referred to herein as“Hsieh enhancers” and are described, for example, in aforementioned U.S.Pat. No. 5,023,252. Such enhancers are lipophilic and are“membrane-compatible”, meaning that they do not cause damage to themembrane on which the composition of the composition of the presentinvention is to be applied (hereafter “target membrane”). Such enhancersproduce also a low level of irritability or no irritability to thetarget membrane and, in fact, serve as an emollient.

Preferred Hsieh enhancers for use in the present invention aremacrocyclic enhancers. The term “macrocyclic” is used herein to refer tocyclic compounds having at least 12 carbons in the ring. Examples ofpreferred macrocyclic enhancers for use in the present inventioninclude: (A) macrocyclic ketones, for example,3-methylcyclopentadecanone (muscone), 9-cycloheptadecen-1-one(civetone), cyclohexadecanone, and cyclopentadecanone (normuscone); and(B) macrocyclic esters, for example, pentadecalactones such asoxacyclohexadecan-2-one (cyclopentadecanolide; ω-pentadecalactone).

Oxacyclohexadecan-2-one and cyclopentadecanone are especially preferred.It has been observed during human clinical testing that only 2 to 4% ofpatients experienced application site events (e.g., erythema) when acomposition of the present invention comprising oxacyclohexadecan-2-onewas applied to a target membrane.

The enhancer is present in the composition in a concentration effectiveto enhance penetration through the membrane of the androgen to bedelivered. Various considerations should be taken into account indetermining the amount of enhancer to use. Such considerations include,for example, the amount of flux (rate of passage through the membrane)achieved and the stability and compatibility of the components in theformulations. For guideline purposes, it is believed most applicationswill involve the use of the enhancer in an amount of about 0.01 to about25 wt. % of the composition, more likely in an amount of about 0.1 toabout 15 wt. % of the composition, and most likely in an amount of about0.5 to about 15 wt. % of the composition.

The composition of the present invention comprises also a thickeningagent for use in increasing the viscosity of the composition. Increasedviscosity retards the flow of the composition, thus allowing forimproved surface cling. Increased viscosity retards also the movement ofparticles dispersed in the composition, allowing for compounds dispersedtherein to remain suspended therein for relatively long periods of time.For guideline purposes, it is believed applications comprisingtestosterone or its precursors, congeners, salts, complexes, or analogswill involve the use of a gel with a viscosity of about 500 to about20,000 cps, more likely about 2,000 cps to about 6,000 cps, and mostlikely about 2,800 cps to about 4,600 cps (as measured under standardconditions of measurement). It is believed applications comprising DHTor its congeners, salts, complexes, or analogs will involve the use of agel with a viscosity of about 1,000 cps to 9,000 cps, more likely about2,000 cps to about 8,000 cps and most like about 3,000 cps to about7,000 cps (as measured under standard conditions of measurement).

Essentially any suitable thickening agent or mixture of thickeningagents can be used in the practice of the present invention. Preferredthickening agents are characterized by at least one of the followingproperties: low level of irritability or no irritability to the targetmembrane; bioadhesiveness; and being listed in the National Formulary orthe U.S. Pharmacopeia. Preferred sources of thickening agents are thosewhich do not include also residual components which may be detrimentalto the membrane, for example, benzene and toluene. In addition,preferred thickening agents are those that are synthetic and notobtained from natural sources, thus reducing the risk of unwantedimpurities.

As stated above, preferred thickening agents for use in the presentinvention include those which produce a low level of irritability or noirritability to the target membrane. Examples of such thickening agentsinclude: cellulosic thickening agents, for example, cellulose,hydroxyethyl-cellulose, carboxymethylcellulose, andhydroxypropylmethyl-cellulose; and acrylic thickening agents. Examplesof preferred acrylic thickeners are carbomers, for example, non-linearpolymers of acrylic acid cross-linked with a polyalkenyl polyether.Examples of preferred carbomers which may be used in the presentinvention include carboxypolymethylene, carboxyvinyl polymer, and alkylacrylates, for example, acrylic acid/alkyl methacrylate copolymer. Allof the above are available from Noveon, with carboxypolymethylene soldas Carbopol 980®, carboxyvinyl polymer sold as Carbopol 940®, andacrylic acid/alkyl methacrylate copolymer sold as Pemulen TR-1®.Additional information regarding the above carbomers is provided inNoveon publications TDS-57, 60, 61, 93, 94, 103, 114, 117, 118, 124,164, 232-3, 237, 244 and TOX-001. In addition, in compositions in whichacrylic acid/alkyl methacrylate copolymer (Pemulen TR-1®) is not used asthe primary thickening agent, it is preferred that such be present as aco-thickening agent. This is because acrylic acid/alkyl methacrylatecopolymer provides the composition with a smoother feel as compared withcompositions which do not use acrylic acid/alkyl methacrylate copolymerand serves also as an emollient.

The thickening agent is present in the composition in a concentrationeffective to provide the desired viscosity to the composition. Forguideline purposes, it is believed most applications will involve theuse of the thickening agent in an amount of about 0.1 to about 10 wt. %of the composition and more likely in an amount of about 1 to about 6wt. % of the composition.

The composition of the present invention may comprise also a carrierwhich is capable of solubilizing one of more of the ingredientscomprising the composition of the present invention. Essentially anysuitable carrier or mixture of carriers which is a suitable vehicle forthe composition of the present invention can be used in the practicethereof. Preferred carriers are characterized by at least one of thefollowing properties: low irritability or no irritability to the targetmembrane; being listed in the National Formulary or the U.S.Pharmacopeia; capability to enhance penetration of the androgen across amembrane; and capability to perform an additional function in thecomposition, for example, function also as an emollient, a humectant, aplasticizer, a lubricating agent, and/or a protein stabilizer.

Essentially any solvent capable of solvating at least one of thecompounds of the composition of the present invention may be used.Alcohols are preferred primary solvents for use in the present inventionbecause they are capable of solvating the active compounds and thethickening agent and, in compositions in which carbomers are used as thethickening agent, serve to swell the thickening agent. It is believedthat alcohols may serve also to enhance the penetration of an androgenacross a membrane. Examples of preferred alcohols are lower alkanols,for example, ethanol and isopropanol since such are capable of rapidevaporation, thus ensuring adequate permeation of the androgen thoughthe target membrane.

Preferred co-solvents include glycerin, propylene glycol, polyethylene,polypropylene, and silicones. In addition to serving as co-solvents,glycerin serves as a humectant, an emollient, a plasticizer whichplasticizes the stratum corneum of the skin, and a permeation enhancerand propylene glycol serves as an emollient and a permeation enhancer.

The carrier is present in the composition in a concentration effectiveto serve as a suitable vehicle for the compositions of the presentinvention. For guideline purposes, it is believed that most applicationswill involve the use of the carrier in an amount of about 40 to about 98wt. % of the composition and more likely in an amount of about 50 toabout 98 wt. % of the composition.

In preferred form, applications will involve the use of a lower alkanolin an amount of at least about 40 wt. % of the composition and generallyabout 40 to about 80 wt. % of the composition, more likely in an amountof about 50 to about 75 wt. % of the composition, and most likely in anamount of about 60 to about 75 wt. % of the composition.

In situations where a greater flux for a certain compound is desired, acarrier may be designed in which a first fluid which is miscible with orsolvates the compound of interest evaporates more readily than a secondfluid, which is immiscible with or partially miscible with or does notsolvate the compound of interest. In such situations, when the firstfluid evaporates, the compound of interest is left in a supersaturatedenvironment in which it is favorable for the compound to pass into aless saturated environment, in this case through the membrane. Forexample, oxacyclohexadecan-2-one is miscible with ethanol, but onlypartially miscible with propylene glycol and immiscible with water.Accordingly, if increased flux for oxacyclohexadecan-2-one is desired, acarrier may include ethanol and propylene glycol and/or water. Asanother example, testosterone is soluble in ethanol but not soluble inwater and partially soluble in propylene glycol. Accordingly, ifincreased flux for testosterone is desired, a carrier may includeethanol and water or ethanol and propylene glycol. In addition, watermay be used to prevent “reverse-flux”, or the flow of water from themembrane into the matrix of the composition.

The composition of the present invention may comprise also acrystallization inhibitor capable of inhibiting the crystallization ofan androgen. Essentially any suitable crystallization inhibitor ormixture of such inhibitors can be used in the practice of the presentinvention. Preferred crystallization inhibitors function by lowering thetemperature at which an androgen crystallizes. An example of such acrystallization inhibitor is polyethylene glycol 1000.

The crystallization inhibitor is present in the composition in aconcentration effective to inhibit the crystallization of the androgen.For guideline purposes, it is believed that most applications whichcomprise a crystallization inhibitor will involve the use of thecrystallization inhibitor in an amount of about 0.001 to about 5 wt. %of the composition, more likely about 0.01 to about 2 wt. % of thecomposition, and most likely about 0.1 to about 1 wt. % of thecomposition.

The composition of the present invention may comprise also apreservative capable of preventing oxidation of the components of thecomposition, microbial growth, or contamination. Essentially anysuitable preservative or mixture of preservatives may be used in thepractice of the present invention. Preferred preservatives include: foodadditive anti-microbial agents, for example, quaternary ammonium salts,sorbic acid, acetic acid, and benzoic acid or salts thereof; andantioxidants, for example, Vitamin C, Vitamin E, butylatedhydroxyanisole (BHA), and butylated hydroxytoluene (BHT). Examples ofpreferred antimicrobial preservatives include benzalkonium chloride andcetyl pyridinium chloride.

The preservative is present in the composition in a concentrationeffective to inhibit microbial growth, the oxidation of the componentsof the composition, or contamination of the composition. For guidelinepurposes, it is believed that most applications which comprise apreservative will involve the use of the preservative in an amount ofabout 0.0001 to about 1.0 wt. % of the composition and more likely in anamount of about 0.005 to about 0.1 wt. % of the composition.

In compositions in which the use of a thickening agent may requireneutralization to achieve a desired thickening for the composition, aneutralizing agent may be included in the composition. Carbomers, asacidic molecules, require neutralization, preferably to a pH of between3 and 9, to achieve their maximum viscosity. Essentially any suitableneutralizing agent or mixture of neutralizing agents can be used in thepractice of the present invention. Preferred neutralizing agents arecharacterized by at least one of the following properties: a pKa greaterthan about 9, with a pKa greater than about 9.5 being particularlypreferred; and being compendial and approved for use by governmentalagencies in pharmaceutical formulations. Examples of the neutralizingagents which exhibit both of the above properties includetriethanolamine, tromethamine, tris amino, triethylamine,2-amino-2-methyl-1-propanol, sodium hydroxide, ammonium hydroxide, andpotassium hydroxide.

The choice of neutralizing agent for use in the present applicationshould take into account the thickening agent used. When a solvent isused, the choice of neutralizing agent should take into account theprimary solvent for the composition and the concentration of the primarysolvent in the composition. If an inappropriate neutralizing agent isused, the thickening agent may precipitate out of solution. Noveonpublication TRS-237 provides a chart showing examples of appropriateneutralizing agents for compositions with certain concentrations ofalcoholic solvent.

The neutralizing agent is present in the composition in a concentrationeffective to provide the desired viscosity to the composition. Forguideline purposes, it is believed that most applications which comprisea neutralizing agent will involve the use of the neutralizing agent inamount which will be sufficient to bring the pH of the composition tobetween about 3 and about 9, more likely between about 4 and about 8.

The composition of the present invention may include also additionaloptional ingredients which are art-recognized and in art-recognizedquantities. For example, materials may be added to modify the rheology,feel, slip, stability, humectancy, fragrance and other desirablephysical properties that a practitioner may deem desirable. In addition,buffers may be added to maintain the composition at a certain pH.

The composition of the present invention may exist in various forms, forexample, a gel, a cream, a lotion, an ointment, or a thickened solution.The composition preferably exists in the form of a gel.

In preferred form, the composition exists in the form of a homogeneousgel which is capable of remaining homogeneous over the pharmaceuticallifetime thereof.

The composition of the present invention preferably exhibits good yieldvalue. Yield value measures the resistance of a composition to breakdown upon stress (e.g., when being rubbed onto skin). The compositionshould preferably also be capable of allowing for a consistentnormalization of androgen delivery into the blood serum over an extendedperiod of time. Additional preferred properties of the compositioninclude emolliency (the producing of a low level of irritability or noirritability to a target membrane), lubricity, and ability to avoidpilling.

The composition of the present invention, when used to delivertestosterone to a male patient, may be delivered in the form of a unitdose formulation which contains testosterone in an amount such that,following a single application of the unit dose to the patient, theamount of circulating testosterone (AUC₀₋₂₄) in the blood serum of thepatient achieved in the 24-hour period following the application isabout 100 to about 35,000 ng·h/dL, preferably about 600 to about 23,500ng·h/dL, and most preferably about 2,900 to about 11,700 ng·h/dL greaterthan the amount of circulating testosterone (AUC₀₋₂₄) in the blood serumof the patient that would have been achieved in the same 24-hour periodhad the dose not been administered. Such a unit dose for male patientswill involve the use of about 1 to about 300 mg of testosterone, morelikely an amount of about 5 to about 200 mg testosterone, and mostlikely in an amount of about 25 to about 100 mg testosterone. Inpreferred form, the unit dose contains up to about 1 wt. % testosterone.

The composition of the present invention, when used to delivertestosterone to a female patient, may be delivered in the form of a unitdose formulation which contains testosterone in an amount such that,following a single application of the unit dose to the patient, theamount of circulating testosterone (AUC₀₋₂₄) in the blood serum of thepatient achieved in the 24-hour period following the application isabout 0.10 to about 11,700 ng·h/dL, preferably about 100 to about 8,800ng·h/dL, and most preferably about 600 to about 6,000 ng·h/dL greaterthan the average testosterone concentration (AUC₀₋₂₄) in the blood serumof the patient that would have been achieved in the same 24-hour periodhad the dose not been administered. Such a unit dose for female patientswill involve the use of about 0.01 to about 100 mg of testosterone, morelikely an amount of about 1 to about 75 mg testosterone, and most likelyin an amount of about 5 to about 50 mg testosterone. In preferred form,the unit dose contains up to about 1 wt. % testosterone.

The composition of the present invention, when used to deliver DHT to amale patient, may be delivered in the form of a unit dose formulationwhich contains DHT in an amount such that, following a singleapplication of the unit dose to the patient, the amount of circulatingDHT (AUC₀₋₂₄) in the blood serum of the patient achieved in the 24-hourperiod following the application is about 11,625 to about 465,000pg·h/mL, preferably about 23,250 to about 232,500 pg·h/mL, and mostpreferably about 46,500 to about 116,250 pg·h/mL greater than the amountof circulating DHT (AUC₀₋₂₄) in the blood serum of the patient thatwould have been achieved in the same 24-hour period had the dose notbeen administered. Such a unit dose for male patients will involve theuse of about 5 to about 200 mg of DHT, more likely an amount of about 10to about 100 mg DHT, and most likely in an amount of about 20 to about50 mg DHT. In preferred form, the unit dose contains up to about 1 wt. %DHT.

The composition of the present invention, when used to deliver DHT to afemale patient, may be delivered in the form of a unit dose formulationwhich contains DHT in an amount such that, following a singleapplication of the unit dose to the patient, the amount of circulatingDHT (AUC₀₋₂₄) in the blood serum of the patient achieved in the 24-hourperiod following the application is about 11.6 to about 232,500 pg·h/mL,preferably about 116 to about 116,250 pg·h/mL, and most preferably about2,325 to about 58,100 pg·h/mL greater than the amount of circulating DHT(AUC₀₋₂₄) in the blood serum of the patient that would have beenachieved in the same 24-hour period had the dose not been administered.Such a unit dose for female patients will involve the use of about 0.005to about 100 mg of DHT, more likely an amount of about 0.05 to about 50mg DHT, and most likely in an amount of about 1 to about 25 mg DHT. Inpreferred form, the unit dose contains up to about 1 wt. % DHT.

The composition of the present invention in gel form may be contained ina tube, a sachet, or a metered pump. Such a tube or sachet may containone unit dose of the composition. A metered pump may be capable ofdispensing one metered dose of the composition.

A condition in a patient related to below-normal androgen concentrationin the blood serum of the patient may be treated by administering to thepatient a composition of the present invention. The composition may bedelivered topically. If the composition is in the form of a gel, thecomposition may be rubbed onto a membrane of the patient, for example,the skin, preferably intact, clean, and dry skin, of the shoulder orupper arm and or the upper torso, and maintained thereon for a period oftime sufficient for delivery of androgen to the blood serum of thepatient.

The dosage amount will depend upon the condition to be treated, thefrequency of administration of the dose, and the amount of androgen inthe composition. For the purpose of treating male hypogonadism, apreferred once daily dosage amount of a 1% testosterone gel of thepresent invention contains about 0.1 to about 30 grams of thecomposition, more preferably about 0.5 to about 20 grams of thecomposition, and most preferably about 2.5 to about 10 grams of thecomposition. A preferred once daily dosage amount of a 1% DHT gel of thepresent invention for the treatment of male hypogonadism contains about0.5 to about 20 grams of the composition, more preferably about 1 toabout 10 grams of the composition, and most preferably about 2 to about5 grams of the composition. For purpose of treating female testosteronedeficiency, a preferred once daily dosage amount of a 1% testosteronegel of the present invention contains about 0.001 to about 10 grams ofthe composition, more preferably about 0.1 to about 7.5 grams of thecomposition, and most preferably about 0.5 to about 5 grams of thecomposition. A preferred once daily dosage amount of a 1% DHT gel of thepresent invention for the treatment of female testosterone deficiencycontains about 0.0005 to about 10 grams of the composition, morepreferably about 0.005 to about 5 grams of the composition, and mostpreferably about 0.1 to about 2.5 grams of the composition. If, after aperiod of time has passed following the initial administration of thecomposition (for example, about 7 to 14 days), the desired clinicalresponse has not been achieved or if the androgen concentration in theblood serum of the patient is determined and found to remain below thenormal adult concentration thereof, the amount of the dose, thefrequency of the dose, and/or the number of applications of the dose maybe increased. Similarly, if, after a period of time has passed followingthe initial administration of the composition (for example, about 7 to14 days), the androgen concentration in the blood serum of the patientis determined and found to be above the normal adult concentrationthereof, the amount of the dose, the frequency of the dose, and/or thenumber of applications of the dose may be decreased.

In situations where a unit dose is applied, one or more of such unitdoses may be administered to a patient, depending upon the condition tobe treated, the amount of androgen to be delivered, and the frequency ofadministration. The number of such unit doses may be increased ordecreased as needed, depending upon, as stated above, whether a desiredclinical effect has been achieved and the concentration of androgen inthe blood serum of the patient treated.

The composition of the present invention may be formulated by the use ofconventional means, for example, by mixing and stirring the ingredients.Conventional equipment may be used. One of the advantages of the presentinvention is the ability to formulate the composition without resortingto unusual means to achieve the desired result. Simple glassware orstainless steel mixing vessels may be used. The composition can beformulated typically at room temperature or slightly above and atatmospheric pressures.

EXAMPLES

The following includes examples of compositions of the present inventionand of comparative compositions.

Example 1

The example below describes the preparation of a composition which canbe used as a topical gel for the delivery of testosterone and which isillustrative of a composition of the present invention. Theconcentrations of the ingredients comprising the composition are givenin percent by weight relative to the total weight of the composition.

Wt. % testosterone, micronized, USP (B&B) 1.0 oxacyclohexadecan-2-one -enhancer 8.0 propylene glycol, USP - co-enhancer 5.0carboxypolymethylene (B F Goodrich; sold as Carbopol 1.5 980 ®) -thickening agent acrylic acid/alkyl methacrylate copolymer 0.3 (B FGoodrich; sold as Pemulen-TR1) - thickening agent ethanol, 200 proof,USP - solvent 73.6 glycerin, USP - co-solvent, emollient, humectant, and5.0 protein stabilizer polyethylene glycol 1000, NF - crystallizationinhibitor 0.5 tris amino crystal - neutralizing agent 0.1 water,sterile, for irrigation, USP 5.0A composition comprising the above ingredients was prepared in a lotsize of 1000 grams. All ingredients were weighed accurately to twodecimal points and then added to a vessel. Oxacyclohexadecan-2-one,ethanol, propylene glycol, and glycerin were weighed in a bottle beaker.All compounding steps took place at approximately 22° C. In between eachstep of addition and during stirring, a teflon stopper was placed on topof the vessel to prevent evaporation.

Eighty grams of oxacyclohexadecan-2-one in solid form were warmed in a40 to 50° C. water bath until molten and added to a vessel. Four-hundredgrams of ethanol were then added to the vessel while using portions torepeatedly rinse out the bottle beaker which containedoxacyclohexadecan-2-one. Fifty grams of propylene glycol and 50 grams ofglycerin were then added separately, in that order, to the vessel andthe resulting mixture was stirred gently using an electric stirrer untilthe solids were free to move. Ten grams of testosterone powder were thenadded to the vessel and the resulting mixture was stirred until thetestosterone was dissolved completely. Five grams of polyethylene glycolwere added thereafter to the vessel and the resulting mixture wasstirred until the polyethylene glycol was dissolved completely. Threegrams of acrylic acid/alkyl methacrylate copolymer and 15 grams ofcarboxypolymethylene were then added separately, in that order, to thevessel and the resulting mixture was then stirred for approximately onehour and twenty minutes. Three hundred and thirty-six grams of ethanolwere then added to the vessel while using portions of the ethanol torepeatedly rinse out the bottle beakers previously used. While stirringthe contents of the vessel, 50 grams of water and 1 gram of tris aminocrystal were combined and weighed in one of the previously used bottlebeakers, shaken until dissolved, and slowly added dropwise over 20minutes to the center of the vessel, near the vortex, using a disposablepolyethylene pipette. Stirring of the resulting mixture continued forapproximately 18 hours. The above order or addition was not critical.There was recovered a colorless, clear to translucent gel with aviscosity of about 3,500 cps (as measured under standard conditions ofmeasurement) and a musk-like fragrance. The gel is capable of beingsqueezed from a tube or a sachet and of being dispensed from a meteredpump.

Example 2

The example below describes the preparation of a composition which canbe used as a topical gel for the delivery of dihydrotestosterone (DHT)and which is illustrative of a composition of the present invention. Theconcentrations of the ingredients comprising the composition are givenin percent by weight relative to the total weight of the composition.

Wt. % dihydrotestosterone (Diosynth) 1.0 oxacyclohexadecan-2-one -enhancer 1.0 propylene glycol, USP - co-enhancer 5.0carboxypolymethylene (B F Goodrich; sold as Carbopol 1.0 980 ®) -thickening agent acrylic acid/alkyl methacrylate copolymer 0.5 (B FGoodrich; sold as Pemulen-TR1) - thickening agent ethanol, 200 proof,USP - solvent 74.0 glycerin, USP - co-solvent, emollient, humectant, and1.0 protein stabilizer polyethylene glycol 400, NF - crystallizationinhibitor 0.25 tris amino crystal - neutralizing agent 0.08 water,sterile, for irrigation, USP 16.17A composition comprising the above ingredients was prepared in a lotsize of 400 grams. All ingredients were weighed accurately to twodecimal points and then added to a vessel. Oxacyclohexadecan-2-one,ethanol, propylene glycol, and glycerin were weighed in a bottle beaker.All compounding steps took place at ambient temperature In between eachstep of addition and during stirring, a teflon stopper was placed on topof the vessel to prevent evaporation.

Four grams of oxacyclohexadecan-2-one in solid form were added to avessel. Ethanol was then added to the vessel while using portions torepeatedly rinse out the bottle beaker which containedoxacyclohexadecan-2-one. Twenty grams of propylene glycol and 4 grams ofglycerin were then added separately, in that order, to the vessel andthe resulting mixture was stirred gently using an electric stirrer untilthe solids were free to move. Four grams of DHT were then added to thevessel and the resulting mixture was stirred until the testosterone wasdissolved completely. One gram of polyethylene glycol was addedthereafter to the vessel and the resulting mixture was stirred until thepolyethylene glycol was dissolved completely. Two grams of acrylicacid/alkyl methacrylate copolymer and 4 grams of carboxypolymethylenewere then added separately, in that order, to the vessel and theresulting mixture was then stirred for approximately one hour and twentyminutes. The remainder of the ethanol (a total of 296 grams of ethanolwas used in the making of this gel) was then added to the vessel whileusing portions of the ethanol to repeatedly rinse out the bottle beakerspreviously used. While stirring the contents of the vessel, 64.68 gramsof water and 0.32 gram of tris amino crystal were combined and weighedin one of the previously used bottle beakers and shaken until dissolved.The above order or addition was not critical.

Example 3

The example below describes the preparation of a composition which canbe used as a topical gel for the delivery of dihydrotestosterone (DHT)and which is illustrative of a composition of the present invention. Theconcentrations of the ingredients comprising the composition are givenin percent by weight relative to the total weight of the composition.This composition is similar to that described in Example 2 except thatslightly less ethanol and slightly greater amounts of glycerin,polyethylene glycol 400, and water were used.

Wt. % dihydrotestosterone (Diosynth) 1.0 oxacyclohexadecan-2-one -enhancer 1.0 propylene glycol, USP - co-enhancer 5.0carboxypolymethylene (B F Goodrich; sold as Carbopol 1.0 980 ®) -thickening agent acrylic acid/alkyl methacrylate copolymer 0.5 (B FGoodrich; sold as Pemulen-TR1) - thickening agent ethanol, 200 proof,USP - solvent 69.6 glycerin, USP - co-solvent, emollient, humectant, and5.0 protein stabilizer polyethylene glycol 400, NF - crystallizationinhibitor 0.5 tris amino crystal - neutralizing agent 0.08 water,sterile, for irrigation, USP 16.32A composition comprising the above ingredients was prepared in a lotsize of 400 grams. All ingredients were weighed accurately to twodecimal points and then added to a vessel. Oxacyclohexadecan-2-one,ethanol, propylene glycol, and glycerin were weighed in a bottle beaker.All compounding steps took place at ambient temperature In between eachstep of addition and during stirring, a teflon stopper was placed on topof the vessel to prevent evaporation.

Four grams of oxacyclohexadecan-2-one in solid form were added to avessel. Ethanol was then added to the vessel while using portions torepeatedly rinse out the bottle beaker which containedoxacyclohexadecan-2-one. Twenty grams of propylene glycol and 20 gramsof glycerin were then added separately, in that order, to the vessel andthe resulting mixture was stirred gently using an electric stirrer untilthe solids were free to move. Four grams of DHT were then added to thevessel and the resulting mixture was stirred until the testosterone wasdissolved completely. Two grams of polyethylene glycol were addedthereafter to the vessel and the resulting mixture was stirred until thepolyethylene glycol was dissolved completely. Two grams of acrylicacid/alkyl methacrylate copolymer and 4 grams of carboxypolymethylenewere then added separately, in that order, to the vessel and theresulting mixture was then stirred for approximately one hour and twentyminutes. The remainder of the ethanol (a total of 278.4 grams of ethanolwas used in the making of this gel) was then added to the vessel whileusing portions of the ethanol to repeatedly rinse out the bottle beakerspreviously used. While stirring the contents of the vessel, 65.28 gramsof water and 0.32 gram of tris amino crystal were combined and weighedin one of the previously used bottle beakers and shaken until dissolved.The above order or addition was not critical.

Comparative Example C-1

The following is the composition of AndroGel®, a topical 1% testosteronegel: testosterone USP (testosterone comprises 1 wt. % of thiscomposition), isopropyl myristate, carboxyvinyl polymer, sodiumhydroxide, purified water, and ethanol (ethanol comprises 67.0 wt % ofthis composition).

The following is a description of the comparative use of the AndroGel®composition (hereafter “C-1 composition”) and a composition of thepresent invention (hereafter “No. 1 composition”). The formulation ofthe No. 1 composition is as described in Example 1 with the exceptionthat tromethamine, and not tris amino, was used as the neutralizingagent. Since large scale production was used to produce the No. 1composition, various process and equipment changes were made asappropriate.

Such appropriate changes are known to those of skill in the art andinclude changes in order of ingredient additions and mixing times. Inaddition, during the manufacturing process an overage of ethanol wasadded for the purpose of compensating for the evaporation thereof whichoccurs when larger equipment is used.

A total of 180 patients were screened for the present study. Twenty-ninehypogonadal male patients (25 Caucasian, 2 Asian, 1 Black, and 1Hispanic) were selected for treatment. The mean age of these patientswas 61.2 (±8.9) years, mean height was 70.2 (±2.7) inches, and meanbody-mass index was 27.1 (±3.1). Nineteen patients had an 0800 h (±30min) testosterone concentration in the blood serum of below 250 ng/dL.Ten patients had an 0900 h (±30 min) testosterone concentration in theblood serum of between 250 and 300 ng/dL. Except for male hypogonadism,the patients were in generally good health as evidenced by medicalhistory, physical examination, clinical laboratory evaluations, andelectrocardiogram obtained within 3 weeks prior to initial study drugadministration. The study was conducted at the Orlando Clinical ResearchCenter, Orlando, Fla. USA.

The present study was conducted as a randomized, open-label, two-waycomplete crossover study. The patients each received a single 5 g doseof the composition of the No. 1 composition and a single 5 g dose of theC-1 composition seven days apart at different body sites (right/leftshoulder). The composition was applied by the patient, using his hands,to intact, clean, and dry shoulder skin and rubbed until dry. Each dosecontained 50 mg testosterone. Approximately 10 mL of whole blood sampleswere collected prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,12, 15, 18, 24, and 48 hours after dosing. The patients were housed andsupervised during each dosing period from approximately 12 hours priorto dosing until after the 24-hour blood collection was completed. The48-hour blood collection was collected the following day.

Serum from the collected blood samples were separated by centrifugationof the blood samples at 1500×g for 10 minutes at 18° C. The resultingsera were transferred into plastic tubes and immediately frozen andstored at −20° C. (±3° C.) until assayed. The assay for totaltestosterone (T) was performed using the Coat-a-Count® TotalTestosterone Assay Kit produced by Diagnostics Products Corporation. Theassay for free testosterone (FT) was performed using the Coat-a-Count®Free Testosterone Assay Kit produced by Diagnostics ProductsCorporation. The assay for dihydrotestosterone (DHT) was performed usingthe Active™ Dihydrotestosterone Assay Kit produced by DiagnosticsSystems Laboratories. All assays were performed by ICON Laboratories,New York, USA.

Serum concentrations of T, FT, and DHT were measured and the maximumconcentrations thereof achieved over the 48-hour period (C_(max)) weredetermined. A serum concentration (not baseline-adjusted) vs. time curvewas plotted for T, FT, and DHT (FIG. 1 shows the curve for T). The areaunder the serum concentration vs. time curve from 0 to 24 hours asdetermined using the linear trapezoidal rule (AUC₀₋₂₄) was measured forT, FT, and DHT. The baseline-adjusted results are summarized in Tables 1to 3 below.

TABLE 1 Baseline Adjusted Total Testosterone - Mean (Standard Deviation)C_(max) and AUC₀₋₂₄ Composition C_(max) (ng/dL) AUC₀₋₂₄ (ng · h/dL) No.1 480 (±70.3) 5864.5 (±77.9) C-1 368 (±60.9) 4499.1 (±77.9)

TABLE 2 Baseline Adjusted Free Testosterone - Mean (Standard Deviation)C_(max) and AUC₀₋₂₄ Composition C_(max) (ng/dL) AUC₀₋₂₄ (ng · h/dL) No.1 20.08 (±77.8) 240.7 (±75.4) C-1 14.55 (±69.8) 164.2 (±90.0)

TABLE 3 Baseline Adjusted Dihydrotestosterone - Median (Range) C_(max)and AUC₀₋₂₄** Composition C_(max) (pg/dL) AUC₀₋₂₄ (pg · h/dL)* No. 1 321(23 to 964)  4891.0 (257.5 to 15259.1) C-1 313 (16 to 1038) 4091.7(225.0 to 16034.5) *One patient was excluded for AUC₀₋₂₄ because therewas insufficient sample volume for analysis in the second period.**Assumptions of normality were not satisfied for ANOVA model.Therefore, non-parametric analysis was performed.

The above values in Tables 1 to 3 were estimated using. WinNonlinpharmacokinetic software. The C_(max) and AUC₀₋₂₄ values above arebaseline-adjusted, with baseline being the pre-dose concentration. Theadjustment for C_(max) was made by subtracting the pre-doseconcentration from the measured concentration. Several negative valueswere generated. These values were imputed with zero unless observed atthe last sampling time point, in which case they were ignored forpharmacokinetic purposes. The adjustment for AUC₀₋₂₄ was made bysubtracting the pre-dose concentration of testosterone in the bloodserum of the patient from the measured concentration thereof at eachsampling time over the 24-hour period (it is assumed that, inhypogonadal patients, the concentration of testosterone over the 24-hourperiod does not vary greatly).

For T, the mean baseline-adjusted C_(max) following administration ofthe No. 1 composition was approximately 30% greater than the meanbaseline-adjusted C_(max) following administration of the C-1composition. For FT, the mean baseline-adjusted C_(max) followingadministration of the No. 1 composition was approximately 38% greaterthan the mean baseline-adjusted C_(max) following administration of theC-1 composition. For DHT, the median baseline-adjusted C_(max) followingadministration of the No. 1 composition was approximately 2.5% greaterthan the median baseline-adjusted C_(max) following administration ofthe C-1 composition.

For T, the mean AUC₀₋₂₄ following administration of the No. 1composition was approximately 30% greater than the mean AUC₀₋₂₄following administration of the C-1 composition. For FT, the meanAUC₀₋₂₄ following administration of the No. 1 composition wasapproximately 45% greater than the mean AUC₀₋₂₄ following administrationof the C-1 composition. For DHT, the mean AUC₀₋₂₄ followingadministration of the No. 1 composition was approximately 20% greaterthan the mean AUC₀₋₂₄ following administration of the C-1 composition.

As can be seen from FIG. 1, normal male adult total testosterone (T)concentrations (300 ng/dL to 100 ng/dL) were sustained over a period oftime following the administration of one 5 gram dose of the No. 1composition.

In the use of the No. 1 and C-1 compositions, three concentration maximawere observed during the 48-hour post-application period. These maximaoccurred at approximately 3- to 4-hours post-application, 8- to 10-hourspost-application, and 18- to 24-hours post application (see FIG. 1).

Comparative Example C-2

The following is the composition which is used in the Androderm® patch,a transdermal patch used for delivering testosterone: testosterone USP;alcohol USP; glycerine USP; glycerol monooleate; methyl laurate;purified water. USP; and acrylic acid copolymer.

The Androderm® patch has six components. Proceeding from the exteriortoward the surface attached to the skin, the system is composed of: (A)a layer of metallized polyester/Surlyn® (an ethylene-methacrylic acidcopolymer/ethylene vinyl acetate backing film with alcohol resistantink); (B) a reservoir containing the above composition; (C) a permeablepolyethylene microporous membrane; and (D) a peripheral layer of acrylicadhesive surrounding the central active drug delivery area of thesystem. Prior to opening of the system and application to the skin, thecentral delivery surface of the system was sealed with a peelablelaminate disc composed of a five-layer laminate containing polyester,polyesterurethane adhesive, aluminum foil, polyesterurethane adhesive,and polyethylene. The disc was attached to and removed with a releaseliner, a silicone-coated polyester film, which was removed before thesystem was used.

The following is a description of the comparative use of thecompositions of Example 1 (the “No. 1 composition”) and of Example C-2(hereafter the “C-2 composition”).

Four hundred six male patients between 20 and 80 years of age weretreated at 43 centers in the United States. The patients werehypogonadal and exhibited morning total testosterone (T) concentrationsat screening of less than or equal to 10.4 nmol/L (as measured at acentral laboratory) and one or more symptoms of low testosterone (e.g.,fatigue, decreased muscle mass, reduced libido, and reduced sexualfunctioning). Except for male hypogonadism, the patients were ingenerally good health. Patients were excluded from the study if they hadany generalized skin irritation or disease that might have interferedwith androgen absorption, had received any estrogen therapy, aluteinizing hormone-releasing hormone antagonist, or human growthhormone therapy, or had a history of drug abuse within 12 months. Alsoexcluded were patients who had used either Viagra® within 30 days, orwere treated with testosterone or anabolic supplements within 6 weeksprior to the study. The characteristics of the patients, as divided bytest group (described below), are summarized in Table 4 below.Compositions identified in Table 4 as “No. 1”, “C-2”, and “placebo” wereadministered to the patients in the test groups as explained in thediscussion which follows Table 4.

TABLE 4 Patient Characteristics No. 1 Groups Placebo 5 g/day 10 g/dayC-2 Group Group Total Demographics No. of patients 99 106 102 99 406 Age(yrs) 58.1 ± 9.7  56.8 ± 10.6 60.5 ± 9.7  56.8 ± 10.8 58.0 ± 10.3 Height(cm) 178 ± 6  178 ± 8  178 ± 6  180 ± 7  179 ± 7  Weight (kg) 95.7 ±13.4 95.7 ± 14.4 95.1 ± 13.5 98.5 ± 15.6 96.2 ± 14.2 BMI* 30.0 ± 3.7 29.9 ± 3.3  29.9 ± 3.8  30.3 ± 3.8  30.0 ± 3.6  Testosterone (nmol/L)†8.1 ± 2.0 8.1 ± 2.2 8.3 ± 2.4 7.9 ± 2.8 8.1 ± 2.3 Cause of MaleHypogonadism Primary (n) 8 7 4 3 22 Secondary (n) 91 98 98 95 382 Aging(%) 70.7 58.1 66.7 61.2 64.1 Normogonadotrophic (%) 19.2 30.5 26.5 31.627.0 Demographic values are expressed as means ± one standard deviationn = number of patients *BMI = body mass index †Testosterone = 8 a.m.serum concentration at screening exam

One hundred-and-six patients received 10 g/day of the No. 1 compositioncontained in two 5 g/day tubes (hereafter the “10 g/day No. 1 group”);99 patients received 5 g/day of the No. 1 composition, contained in one5 g/day tube, and 5 g/day of a placebo gel, contained in another 5 g/daytube (hereafter the “5 g/day No. 1 group”); 102 patients were treatedusing two Androderm® patches a day, each patch containing the C-2composition with 12.2 mg testosterone and each delivering approximately2.5 mg/day testosterone for a total dosage of approximately 5.0 mg/daytestosterone (hereafter the “C-2 group”); and 99 patients received 10g/day of the above placebo gel contained in two 5 g/day tubes (hereafterthe “placebo group”). The placebo gel was modeled after the gel of theNo. 1 composition with the exception that testosterone is not presentand additional ethanol was added. The study was double-blinded for theNo. 1 groups and the placebo group and open-label for the C-2 group.

All study drug treatments were applied in the morning and repeatapplications occurred at the same time of day for the duration of thestudy. Each of the patients in the No. 1 groups and the placebo groupapplied the contents of two tubes a day with the contents of one tubeapplied to the skin of one shoulder and the contents of the other tubeapplied to the skin of the other shoulder. Patients allocated to receivethe C-2 composition-containing patches applied two adhesive patchesdaily. Application sites included intact and clean skin of the back,abdomen, upper arms, and thighs. Patches were to be worn for 24 hoursand then replaced each morning at approximately the same time.

Forty-four percent of the patients assigned originally to apply 5 g/dayof the No. 1 composition had a mean total testosterone concentration(C_(avg)) on Day 30 of less than 10.4 nmol/L (300 ng/dL) and were thustitrated on Day 60 to a dose of 10 g/day of said composition. Fourpercent of the patients assigned originally to apply 10 g/day of the No.1 composition had a C_(avg) on Day 30 of greater than 34.7 mmol/L (1,000ng/dL) and were thus titrated on Day 60 to a dose of 5 g/day of saidcomposition.

Ninety percent of the patients in the No. 1 groups, 92% of the patientsof the placebo group, and 75% of the patients in the C-2 group completedthe 90-day study. The primary reason for the higher rate ofdiscontinuations in the C-2 group was adverse events (17%), with themajority of events being related to skin irritations at the patch site.Study protocol compliance was 94.9% for the placebo group, 95.5% for theC-2 group, and 97.1% for the No. 1 group. Ninety-three percent ofpatients had a compliance of 80% or greater.

A baseline 24-hour profile for total testosterone (T), free testosterone(FT), and dihydrotestosterone (DHT) concentrations in the blood serumwas measured for the patients using serum samples taken over a 24-hourperiod at 0, 2, 4, 8, 12, and 24 hours on the day immediately prior tothe day of the first dose of the study drug. On Days 30 and 90, thepatients had a 24-hour profile for T, FT, and DHT concentrations in theblood serum measured using data collected from serum samples takenpre-dose and at 2, 4, 8, 12, and 24-hours after drug administration. Themean total testosterone concentration over the 24-hour period (C_(avg)),the minimum testosterone concentration during the 24-hour period(C_(min)), and the maximum testosterone concentration during the 24-hourperiod (C_(max)) were measured. The results are summarized in Tables 5and 6.

The assay for T was performed using the Coat-a-Count® Total TestosteroneAssay Kit produced by Diagnostics Products Corporation. The assay for FTwas performed using the Coat-a-Count® Free Testosterone Assay Kitproduced by Diagnostics Products Corporation. The assay for DHT wasperformed using the Active™ Dihydrotestosterone Assay Kit produced byDiagnostics Systems Laboratories.

Table 5 below shows total testosterone (T) concentrations for the abovegroups measured prior to treatment (baseline) and at Days 30 and 90.

TABLE 5 Testosterone Pharmacokinetics Testosterone (nmol/L): Mean Days30 and 90 No. 1 Groups 5 g/day 10 g/day C-2 Group Placebo Group Day 30C_(avg) baseline 8.6 ± 2.8 7.8 ± 2.8 8.2 ± 2.8 7.5 ± 2.8 actual 12.7 ±6.5   21.3 ± 9.9*** 12.7 ± 4.2  7.5 ± 2.8 C_(min) baseline 6.8 ± 2.4 6.2± 2.6 6.7 ± 2.3 5.9 ± 2.3 actual  7.7 ± 4.4*  13.6 ± 6.5*** 6.2 ± 2.95.7 ± 2.2 C_(max) baseline 10.7 ± 3.6  9.9 ± 3.2 10.2 ± 3.7  9.5 ± 3.6actual  18.8 ± 12.9*  31.2 ± 19.8*** 18.8 ± 6.9  9.4 ± 3.8 Day 90C_(avg) baseline 9.2 ± 3.4 7.7 ± 2.4 8.3 ± 2.8 7.6 ± 2.8 actual 13.8 ±8.1   17.1 ± 8.2*** 11.9 ± 4.6  7.3 ± 2.7 C_(min) baseline 7.4 ± 2.8 6.1± 2.3 6.7 ± 2.1 6.0 ± 2.4 actual   8.7 ± 3.9***  10.9 ± 6.0*** 5.7 ± 2.85.9 ± 2.4 C_(max) baseline 11.3 ± 4.1  9.8 ± 2.9 10.3 ± 3.7  9.5 ± 3.6actual 19.5 ± 12.2   24.4 ± 13.8*** 18.5 ± 8.2  9.1 ± 3.5 Values areexpressed as means ± one standard deviation Change from baselinesignificant versus C-2 group *p < 0.05, ***p < 0.001

For total testosterone (T), at baseline mean C_(avg) for all groups werebelow the normal adult male range (10.4 to 34.7 nmol/L). By Day 30, themean C_(avg) for the 5 g/day No. 1 group had increased about 50% overbaseline with a similar increase being evidenced in the C-2 group andthe mean C_(avg) for the 10 g/day No. 1 group had increased about 173%over baseline (a significant difference (P<0.001) as compared to the C-2group). C_(avg) for the placebo group did not change. The degree offluctuation during a day in total testosterone values([C_(max)−C_(min)]/C_(avg)) was significantly smaller in the two No. 1groups as compared to the C-2 group. The mean C_(min) was significantlyincreased in both the No. 1 groups while C_(min) for the C-2 groupdeclined. By Day 90, similar results were seen across the treatmentgroups. Approximately 75% of the patients in the 5 g/day No. 1 group and80% of the patients in the 10 g/day No. 1 group had C_(avg) values above10.4 nmol/L. By contrast, 57% of the patients in the C-2 group and 10%of the patient in the placebo group had C_(avg) values above 10.4nmol/L. The mean C_(min) were significantly increased in both the No. 1groups while C_(min) declined in the C-2 group.

Table 6 below shows serum dihydrotestosterone concentrations for theabove groups measured prior to treatment (baseline) and at Days 30 and90.

TABLE 6 Dihydrotestosterone Pharmacokinetics Dihydrotestosterone(nmol/L): Mean Days 30 and 90 No. 1 Groups 5 g/day 10 g/day C-2 GroupPlacebo Group Day 30 C_(avg) baseline 0.4 ± 0.2 0.4 ± 0.2 0.4 ± 0.2 0.3± 0.2 actual 1.2 ± 0.7*** 1.9 ± 1.0*** 0.6 ± 0.3 0.4 ± 0.2 C_(min)baseline 0.3 ± 0.1 0.3 ± 0.1 0.3 ± 0.1 0.2 ± 0.1 actual 0.8 ± 0.6*** 1.4± 0.9*** 0.4 ± 0.2 0.3 ± 0.2 C_(max) baseline 0.5 ± 0.2 0.5 ± 0.3 0.5 ±0.3 0.5 ± 0.2 actual 1.7 ± 1.0*** 2.6 ± 1.4*** 0.8 ± 0.7 0.5 ± 0.3 Day90 C_(avg) baseline 0.5 ± 0.2 0.4 ± 0.2 0.4 ± 0.2 0.4 ± 0.2 actual 1.5 ±0.7*** 1.8 ± 0.9*** 0.6 ± 0.3 0.4 ± 0.2 C_(min) baseline 0.3 ± 0.1 0.2 ±0.1 0.3 ± 0.1 0.3 ± 0.1 actual 1.0 ± 0.6*** 1.2 ± 0.7*** 0.3 ± 0.2 0.3 ±0.2 C_(max) baseline 0.6 ± 0.2 0.5 ± 0.2 0.5 ± 0.2 0.5 ± 0.2 actual 2.0± 0.9*** 2.3 ± 1.2*** 0.8 ± 0.4 0.5 ± 0.3 Values are expressed as means± one standard deviation Change from baseline significant versus C-2group ***p < 0.001

For DHT, at baseline mean C_(avg) for all groups were below the normaladult male range (0.9 to 2.6 nmol/L). Mean changes in C_(avg) frombaseline to Day 30 for the 5 g/day and 10 g/day No. 1 groups were overfour- and seven-fold greater, respectively, than changes observed in theC-2 treatment group (P<0.001 for each comparison). In addition, C_(min)in both of the No. 1 groups was increased to a significantly greaterdegree than C_(min) in the C-2 group (P<0.001 for each comparison).

Total body mass (TBM), lean body mass (LBM), fat mass (FM) andpercentage fat (% F) were measured for the above patients using dualenergy x-ray absorptiometry (DXA) on the day immediately prior to theday of the first dose of the study drug and on Day 90 (the results areshown in FIG. 2). The measurements were centrally monitored and analyzedby Synarc, Inc. (Maynard, Mass., U.S.A.). At Day 90, LBM in the 10 g/dayNo. 1 group increased to a significantly greater degree than in the C-2or the placebo group (P<0.05 for each comparison) with mean changes frombaseline of 1.5±4.5, 1.7±2.6, 0.9±1.8, and 0.6±1.8 kg for the 5 g/dayNo. 1 group, 10 g/day No. 1 group, C-2 group, and placebo group,respectively. With the exception of the placebo group, all groupsexhibited decreases in FM which were significant as compared to placebo(P<0.01). Reductions of 0.8±2.4, 0.8±2.0, 0.4±1.8, and 0.1±1.5 kg werenoted in the 5 g/day No. 1 group, 10 g/day No. 1 group, C-2 group, andplacebo group, respectively.

The incidence of treatment-related adverse events was 29.1%, 36.9%,62.7%, and 40.4% in the 5 g/day No. 1 group, 10 g/day No. 1 group, C-2group, and placebo group, respectively. While treatment in the No. 1groups and the placebo group was relatively well tolerated over the90-day study period, the C-2 group patients experienced a substantiallyhigher rate of adverse events. Those most commonly seen wereapplication-site erythema, application-site rash, application-sitepruritus, application-site reactions, and application-site irritation.

No patients in the No. 1 groups discontinued due to skin reaction;whereas, 15% of patients discontinued in the C-2 group as a result oflocal dermal site reactions.

FIG. 3 provides a graphic illustration of the frequency distribution ofpatients having positive skin irritation scores. The scoring system wasbased on a five-point categorical series from 0 (no erythema) through 4(intense erythema with edema and blistering/erosion). As can be seen,events occurred predominately in the C-2 group and only a few mildreactions occurred in the No. 1 and placebo groups. Additionally, thefigure illustrates that the C-2-containing patches acted as an irritantin some patients who experienced classic signs of contact dermatitis andthat the No. 1 group did not experience any more skin irritation thanthe placebo group.

1. A method for maintaining a therapeutically effective concentration oftestosterone in the blood serum of a male for treating hypogonadismwhich comprises transdermally delivering to the male by applying to theskin a composition which is in the form of a topical gel, which has aviscosity of about 2000 to about 6000 cps and a pH of about 4 to about8, and comprises: (A) about 0.1 to about 5 wt. % of testosterone; (B)about 0.5 to about 15 wt. % of oxacyclohexadecan-2-one; (C) about 1 toabout 6 wt. % of a thickening agent; (D) a mixture of solvents whichinclude: (i) about 60 to about 75 wt. % of ethanol or isopropanol; and(ii) propylene glycol and glycerin as co-solvents; and (E) acrystallization inhibitor that is capable of inhibiting crystallizationof testosterone.
 2. The method of claim 1 wherein the crystallizationinhibitor comprises about 0.001 to about 5 wt. % of polyethylene glycol.3. The method of claim 2 wherein said composition is maintained on saidskin for a period of time sufficient for delivery of the testosterone tothe body of the male and is applied to the skin in the form of a unitdose which contains about 1 to about 300 mg of testosterone and suchthat, following a single application of the unit dose to the skin, theamount of circulating testosterone (AUC₀₋₂₄) in the blood serum of themale achieved in the 24-hour period following the application is about100 to about 35,000 ng·h/dL greater than the amount of circulatingtestosterone (AUC₀₋₂₄) in the blood serum of the male than would havebeen achieved in the same 24-hour period had the dose not beenadministered.
 4. A method for maintaining a therapeutically effectiveconcentration of testosterone in the blood serum of a male for treatinghypogonadism which comprises transdermally delivering to the male byapplying to the skin a composition which is in the form of a topicalgel, which has a viscosity of about 2000 to about 6000 cps and a pH ofabout 4 to about 8, and comprises: (A) about 0.1 to about 5 wt. % oftestosterone; (B) about 0.5 to about 15 wt. % ofoxacyclohexadecan-2-one; (C) about 1 to about 6 wt. % of a thickeningagent; (D) a mixture of solvents which include: (i) about 60 to about 75wt. % of ethanol or isopropanol; and (ii) propylene glycol and glycerinas co-solvents; and (E) a crystallization inhibitor that is capable ofinhibiting crystallization of testosterone, wherein said composition ismaintained on said skin for a period of time sufficient for delivery ofthe testosterone to the body of the male and is applied to the skin inthe form of a unit dose which contains about 1 to about 300 mg oftestosterone and such that, following a single application of the unitdose to the skin, the amount of circulating testosterone (AUC₀₋₂₄) inthe blood serum of the male achieved in the 24-hour period following theapplication is about 100 to about 35,000 ng·h/dL greater than the amountof circulating testosterone (AUC₀₋₂₄) in the blood serum of the malethan would have been achieved in the same 24-hour period had the dosenot been administered.
 5. The method of claim 4 wherein thecrystallization inhibitor comprises about 0.001 to about 5 wt. % ofpolyethylene glycol.